JPH0656873A - Erythromycin derivative - Google Patents

Abstract

PURPOSE:To provide a new compound resistant to acid, having an extremely low decomposition rate with gastric acid by oral administration, exhibiting excellent action to promote the contraction motion of alimentary canals and useful as an agent for promoting the contraction motion of alimentary canals. CONSTITUTION:The compound of formula I [R1 is H or an acyl; R2 and R3 are H, amino, etc.; R4 is H or a lower alkyl; Y is NR5R6 or N<+>R7R8R9X<-> (R5 to R9 are each a lower alkyl, lower alkenyl, etc.; X is an anion)], e.g. 2'-O- acetyl-4''-O-formyl-11-oxo-8,9-anhydroerythromycin A6,9-hemiketal. The compound can be produced e.g. by oxidizing a compound of formula II with an oxidizing agent such as chromic acid and manganese oxide and alkylating the product with an alkylation agent such as alkyl halide and acrylic acid derivative in an inert solvent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an erythromycin derivative or a salt thereof which exhibits a contractile motility promoting action on the digestive tract of mammals and is useful as a digestive tract contractile motility promoter.

[0002]

BACKGROUND ART Gastrointestinal motility enhancers are direct acetylcholine agonists such as acratonium napadisylate, indirect acetylcholine agonists such as cisapride, from the viewpoint of action,
It is broadly divided into four types: dopamine blockers such as domperidone and opiate agonists such as trimebutine maleate, and is widely used as a remedy for digestive tract dysfunction such as gastrointestinal dysfunction due to hypokinesia. Has been. However, these drugs are accompanied by side effects such as extrapyramidal symptom due to dopamine blocking action and increased milk secretion. In addition, the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiological movement of the upper gastrointestinal tract to the lower gastrointestinal tract, and is often accompanied by side effects such as diarrhea and vomiting. Are known.

On the other hand, motilin is known as a gastrointestinal hormone that stimulates the contractile movement of the gastrointestinal tract, but the supply of motilin by extraction from nature and chemical synthesis was not satisfactory, and it was difficult to supply it in large quantities. Further, since motilin is a peptide consisting of 22 amino acids, it was difficult to develop it as an oral preparation.

Recently, it has been found that erythromycin and its derivatives have a strong activity to promote gastrointestinal contraction and motility, and one of the derivatives, EM-523, is under development as a gastrointestinal motility promoter (Japanese Patent Laid-Open No. 60-61). -218321
No. 61-87625, 63-9901.
6, JP-A-63-99092 and The Jou.
rnal of Pharmacology and
EXPERIMENTAL THERAPEUTICS
Vol. 251, No. 2, pp. 707-712,
1989).

[0005]

[Problems to be Solved by the Invention] However, EM-5
23 is acid-labile and, when used orally, is expected to be decomposed by gastric acid to have a weakened action. Therefore,
The present inventors have conducted extensive studies to find an acid-resistant orally administrable erythromycin derivative, and as a result, found that the following novel erythromycin derivatives, which have not been described in the literature, have such properties and actions, The present invention has been completed based on this finding.

[0006]

Means for Solving the Problems That is, the present invention provides the following general formula (I):

[Chemical 2] Wherein R ₁ represents a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group, an amino group or together = O, = NOR ₁₀
Indicates. Here, R ₁₀ represents a hydrogen atom or a lower alkyl group. R ₄ is a hydrogen atom or a lower alkyl group, Y is -NR ₅ R ₆ or ^{_{-N + R 7 R 8 R 9}} X - indicating each. Here, R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each may have a hydrogen atom or a substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group or A heterocyclic group having a 3- to 7-membered ring containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom, and X represents an anion. Also, R ₅ and R
₆ , R ₇ and R ₈ may together form an azacycloalkyl group with the adjacent nitrogen atom. ]
And a salt thereof.

In the present invention, the acyl group means a formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, etc. Represents a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, a pivaloyloxy group, a benzoyloxy group, an ethoxycarbonyloxy group, a t-butoxycarbonyloxy group, a benzyloxycarbonyloxy group, etc., and a lower alkyl group Represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, n
-Propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, neopentyl group, etc., and the lower alkenyl group means a straight chain having 2 to 6 carbon atoms or It shows a branched alkenyl group, preferably a vinyl group, an allyl group, an n-butenyl group, an i-butenyl group, a sec-butenyl group, etc., and a lower alkynyl group means a straight chain having 2 to 6 carbon atoms or It shows a branched alkynyl group, preferably an ethynyl group, a propargyl group, a butynyl group and the like.

The azacycloalkyl group means a group in which one or more carbon atoms of a cycloalkyl group are replaced with nitrogen atoms, and examples thereof include aziridinyl group, azetidinyl group,
Examples thereof include pyrrolidinyl group, piperidinyl group and hexamethyleneimino group. The cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like. Examples of the heterocyclic ring of a 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom include:
Examples thereof include aziridine, azetidine, pyrrolidine, piperidine, oxirane, oxetane, oxolane, tetrahydropyran, thiirane, thietane, thiolane and thian.

A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group which may have a substituent, or a 3- to 7-membered heterocycle containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom. Examples of the substituent in the ring group include a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group, an acyl group, and a carbamoyl group, and an oxygen atom, a nitrogen atom or a cycloalkyl group or a hetero atom. Substituents in the 3- to 7-membered heterocyclic group containing a sulfur atom also include hydrocarbon groups such as lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group and aralkyl group.

Anions are chlorine ions, bromine ions,
Iodine ion, carboxylate ion, sulfonate ion and the like are shown. Examples of the acid forming a salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid and methanesulfonic acid.

The compound (I) of the present invention can be produced, for example, by subjecting the compound (II) to an oxidation reaction, and then optionally performing alkylation or deprotection.

[0012]

[Chemical 3] [In the formula, R ₁ , R ₂ , R ₃ , R ₄ and Y have the same meanings as described above].

Examples of the oxidizing agent used in the oxidation reaction include metal oxidizing agents such as chromic acid and manganese oxide, and oxidizing agents using organic compounds such as dimethyl sulfoxide. Alkylation can be carried out by reacting an alkylating agent such as an alkyl halide or an acrylic acid derivative in an inert solvent in the presence or absence of a base. Examples of the base include metal bases such as sodium hydride, sodium alkoxide, potassium alkoxide, alkyllithium, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide and sodium hydroxide, triethylamine, trimethylamine, diisopropylethylamine and pyridine. Of organic bases are used. As the inert solvent, methanol, ethanol, propanol, chloroform, methylene chloride, ether,
Tetrahydrofuran, N, N-dimethylformamide and the like are used. What is an alkyl group in an alkyl halide?
Shows an optionally branched carbon chain having 1 to 6 carbon atoms which may have a substituent such as a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group and a formyl group. , Chlorides, bromides and iodides of the above alkyl groups are used as the alkyl halide,
As the acrylic acid derivative, acrylic acid, acrylic acid ester, acrylonitrile, acrolein or the like is used.

As is clear from the test examples described below, the compound (I) of the present invention, unlike EM-523, does not show a decrease in activity under acidic conditions, and when administered orally, has a strong action to promote gastrointestinal motility. From the above, it is particularly useful as an oral agent as a contractile motility promoter for the digestive tract of mammals.

Hereinafter, the production of the compound of the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[0016]

Example 1 2'-O-acetyl-4 "-O-formyl-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 1) [Reference: J. Tadanier
Et al, Journal of Organic Chem
methylene chloride 400 which is a mixture of 25 g of istry, 39, 2495 (1974)], 24.6 ml of dimethyl sulfoxide, and 19.7 g of dicyclohexylcarbodiimide.
To the ml solution, 18.4 g of pyridinium trifluoroacetate was added under ice cooling. After stirring at room temperature for 4 hours, the insoluble material was filtered. The filtrate was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (30: 1: 0.1)].
White powder 1 of 2′-O-acetyl-4 ″ -O-formyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 2)
6.8 g (yield 67%) was obtained.

[0017]

[Chemical 4]

[0018]

Example 2 A solution of compound 2 (15.8 g) in dimethylformamide (300 ml) was ice-cooled, 60% sodium hydride (1.20 g) was added under stirring, and after stirring for 20 minutes, methyl iodide 2 was added. 0.5 ml was added. The mixture was stirred as it was for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was dissolved in 150 ml of methanol, 10 ml of saturated aqueous sodium hydrogencarbonate was added, and the mixture was stirred overnight at room temperature. The reaction solution was extracted with chloroform, washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (6
0: 1: 0.1)] and 12-O-methyl-1.
1-oxo-8,9-anhydroerythromycin A
7.4 g of white powder of 6,9-hemiketal (Compound 3)
(Yield 51%) was obtained.

[0019]

[Chemical 5]

[0020]

Example 3 50 ml of 80% methanol / water 90 ml solution of compound 3 (6.9 g) and sodium acetate 3.9 g was added.
The mixture was heated to ℃, and iodine (3.6 g) was added with stirring. The solution was stirred at this temperature for 2 hours, during which the solution was adjusted to pH 8-9.
A suitable amount of 1N sodium hydroxide aqueous solution was added in order to maintain The reaction solution is water 350 containing 7 ml of concentrated aqueous ammonia.
The mixture was poured into ml, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (40: 1: 0.1)].
Purified by de (N-methyl) -12-O-methyl-1
1-oxo-8,9-anhydroerythromycin A
White powder of 6,9-hemiketal (Compound 4) 5.21
g (yield 77%) was obtained.

[0021]

[Chemical 6]

[0022]

Example 4 Compound 4 (160 mg) was added to methanol (5 m).
It was dissolved in 1 and 290 mg of diisopropylethylamine and 1.4 g of ethyl iodide were added and stirred at 40 ° C. for 20 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (80: 1: 0.1)] to obtain ethyl-nor-1.
105 mg (yield 63%) of white powder of 2-O-methyl-11-oxo-8,9-anhydroerythromycin A6,9-hemiketal (Compound 5) was obtained.

[0023]

[Chemical 7]

[0024]

Example 5 Compound 4 (485 mg) was added to methanol 10
Dissolve in ml, diisopropylethylamine 877mg
And 4.62 g of isopropyl iodide were added, and the mixture was stirred at 60 ° C. for 5 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] to give isopropyl-nor-12-O-methyl-11-oxo-8, 9
-262 mg (yield 50%) of white powder of anhydroerythromycin A 6,9-hemiketal (Compound 6) was obtained.

[0025]

[Chemical 8]

[0026]

Example 6 Compound 4 (250 mg) was added to methanol (4 m).
It was dissolved in 1 and 453 mg of diisopropylethylamine and 2.38 g of 1-iodopropane were added and stirred at 50 ° C. for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give propyl-
170 mg (yield 64%) of white powder of nor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 7) was obtained.

[0027]

[Chemical 9]

[0028]

Example 7 Compound 4 (250 mg) in methanol (4 m)
It was dissolved in 1 l, and 59 mg of sodium hydrogen carbonate and 0.050 ml of allyl bromide were added, and the mixture was stirred at 40 ° C overnight. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off.
The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (15
0: 1: 0.1)] and allyl-nor-12-
O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 8) was obtained as a white powder (156 mg, yield 59%).

[0029]

[Chemical 10]

[0030]

Example 8 Compound 4 (250 mg) was added to methanol 4 m.
The resulting mixture was dissolved in 1 l, sodium hydrogencarbonate 59 mg and propargyl bromide 0.034 ml were added, and the mixture was stirred at 50 ° C. for 2 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (50: 1: 0.1)] to prepare propargyl-.
105 mg (yield 40%) of white powder of nor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 9) was obtained.

[0031]

[Chemical 11]

[0032]

Example 9 Compound 4 (250 mg) was added to methanol (4 m).
It was dissolved in 1, and 453 mg of diisopropylethylamine and 1.41 g of 4-bromo-1-butene were added, and the mixture was heated to 50 ° C.
Was stirred for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give 3-butenyl-nor-12-O-methyl-11-oxo-. 8,
152 mg of white powder of 9-anhydroerythromycin A 6,9-hemiketal (Compound 10) (yield 56
%) Was obtained.

[0033]

[Chemical 12]

[0034]

Example 10 Compound 4 (250 mg) was added to methanol 4
Dissolve in ml, diisopropylethylamine 453mg
And 1.75 g of bromoethanol were added, and the mixture was stirred at 50 ° C. for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (80: 1: 0.1)] to give 2-hydroxyethyl-nor-12-O-methyl-11-oxo. −
205 mg of a white powder of 8,9-anhydroerythromycin A 6,9-hemiketal (Compound 11) (yield 7
7%).

[0035]

[Chemical 13]

[0036]

Example 11 A solution of compound 4 (270 mg) in 3 ml of acrylonitrile was heated under reflux for 3 hours. After distilling off the solvent, the reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off.
The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (20
0: 1: 0.1)] and white powder of 2-cyanoethyl-nor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 12). 189 mg (yield 65%) was obtained.

[0037]

[Chemical 14]

[0038]

Example 12 75 ml of absolute ethanol was placed in a reaction vessel, and nitrogen was evacuated for 20 minutes. Next, 161 mg of metallic sodium was added, and when the sodium was dissolved, the solution was cooled with ice. Subsequently, compound 4 (1.0 g) was added, and further 1.78 g of iodine was added. After stirring under ice-cooling for 4 hours in a nitrogen atmosphere, the reaction liquid was water 300 containing 3.0 g of sodium thiosulfate and 2.5 ml of concentrated ammonia water.
Injected into ml. This mixed solution was extracted with chloroform, washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-
Concentrated aqueous ammonia (50: 1: 0.1)] and purified to give bis [de (N-methyl)]-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9.
890 mg of white powder of hemiketal (compound 13)
(Yield 90%) was obtained.

[0039]

[Chemical 15]

[0040]

Example 13 Compound 13 (700 mg) was dissolved in 10 ml of methanol, 336 mg of sodium hydrogen carbonate and 3.1 g of ethyl iodide were added, and the mixture was stirred at 50 ° C. for 6 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off.
The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated ammonia water (12
0: 1: 0.1)] and diethyl-dinor-1.
2-O-methyl-11-oxo-8,9-anhydroerythromycin A6,9-hemiketal (Compound 14)
74 mg (10% yield) of white powder of ethyl-dinor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 15) and 172 mg of white powder (24 yield). %) Was obtained.

[0041]

[Chemical 16]

[0042]

Example 14 Compound 13 (995 mg) was dissolved in 20 ml of methanol to prepare diisopropylethylamine 3.6.
7 g and 1.72 g of allyl bromide were added, and the mixture was stirred at 50 ° C. for 10 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (200: 1: 0.1)] to give diallyl-dinor-12-O-methyl-11-oxo-8, 9
-Anhydroerythromycin A 6,9-hemiketal (Compound 16) white powder 490 mg (44% yield)
Got

[0043]

[Chemical 17]

[0044]

Example 15 Compound 13 (440 mg) was dissolved in 10 ml of methanol, 158 mg of sodium hydrogen carbonate and 0.11 ml of allyl bromide were added, and the mixture was stirred at 50 ° C. for 3 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] to give allyl-dinor-12-O-methyl-11-oxo-8, 80 mg (yield 17%) of white powder of 9-anhydroerythromycin A 6,9-hemiketal (Compound 17) was obtained.

[0045]

[Chemical 18]

[0046]

Example 16 Compound 6 (180 mg) and 98 mg of sodium acetate were added to a solution of 3% of 80% methanol / water (5 ml).
After heating to 0 ° C., 91 mg of iodine was added under stirring.
The solution was stirred at this temperature for 2 hours, during which time the solution was adjusted to pH 8
In order to keep at 9, an appropriate amount of 1N sodium hydroxide aqueous solution was added. The reaction solution is water 20 containing 1 ml of concentrated ammonia water.
The mixture was poured into ml, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (80: 1: 0.1)].
White powder 7 of isopropyl-dinor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 18) purified by
0 mg (40% yield) was obtained.

[0047]

[Chemical 19]

[0048]

Example 17 Compound 3 (250 mg) was dissolved in 3 ml of chloroform, 0.096 ml of methyl iodide was added, and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent from the reaction solution,
Ether was added and the resulting precipitate was filtered. The precipitate is washed with ether, dried and 12-O-methyl-11-oxo-
White powder of 8,9-anhydroerythromycin A 6,9-hemiketal methyl iodide (Compound 19) 2
06 mg (yield 69%) was obtained.

[0049]

[Chemical 20]

[0050]

Example 18 Compound 3 (250 mg) was dissolved in 3 ml of chloroform, 0.21 ml of propargyl bromide was added, and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off from the reaction solution, ether was added and the resulting precipitate was filtered. After washing the precipitate with ether, silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (1
0: 1: 0.1)] and 12-O-methyl-1.
1-oxo-8,9-anhydroerythromycin A
6,9-hemiketal propargyl bromide (compound 2
198 mg (yield 68%) of white powder of 0) was obtained.

[0051]

[Chemical 21]

[0052]

Example 19 A solution of compound 3 (694 mg) in 10 ml of chloroform was ice-cooled, and pyridine (0.30) was added under stirring.
ml followed by 0.30 ml acetic anhydride. 1 with ice cooling
The mixture was stirred for 5 minutes and further stirred at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off. To a solution of a mixture of the obtained residue, 0.73 ml of dimethyl sulfoxide and 588 mg of dicyclohexylcarbodiimide in 10 ml of methylene chloride, 550 mg of pyridinium trifluoroacetate was added under ice cooling. After stirring at room temperature for 4 hours, the insoluble material was filtered. The filtrate was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (200: 1: 0.
1)] and 2′-O-acetyl-12-O-methyl-4 ″, 11-dioxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 21).
As a result, 428 mg (yield 58%) of white powder of was obtained.

[0053]

[Chemical formula 22]

[0054]

Example 20 A solution of compound 21 (383 mg) in 5 ml of methanol was stirred at room temperature for 20 hours. The solvent was distilled off from the reaction solution, and the resulting residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (200: 1: 0.1)] to give 12-O-.
Methyl-4 ″, 11-dioxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 2
294 mg (yield 81%) of white powder of 2) was obtained.

[0055]

[Chemical formula 23]

[0056]

Example 21 Compound 2 (2.15 g) was added to methanol 3
The mixture was dissolved in 0 ml, saturated aqueous sodium hydrogen carbonate solution (3 ml) was added, and the mixture was stirred overnight at room temperature. The reaction solution was extracted with chloroform, washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (70: 1: 0.1)] to give 11-oxo-8,9-anhydroerythromycin A 6,9-. 1.84 g (yield 93%) of white powder of hemiketal (Compound 23) was obtained.

[0057]

[Chemical formula 24]

[0058]

Example 22 A solution of the compound 23 (656 mg) and 377 mg of sodium acetate in 10 ml of 80% methanol / water was heated to 50 ° C., and 350 mg of iodine was added under stirring. The mixture was stirred at this temperature for 2 hours, and an appropriate amount of 1N sodium hydroxide aqueous solution was added thereto in order to maintain the pH of the solution at 8-9. The reaction solution was poured into 50 ml of water containing 3 ml of concentrated aqueous ammonia, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (30: 1:
0.1)] to obtain 428 mg (yield 66%) of white powder of de (N-methyl) -11-oxo-8,9-anhydroerythromycin A6,9-hemiketal (Compound 24). . FAB-MS: m / z 701 (MH
⁺ ).

Compound 24 (205 mg) was added to methanol 5
Dissolve in ml, diisopropylethylamine 378mg
And 1.83 g of ethyl iodide were added and the mixture was added at 20 ° C. for 20
I stirred the time. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (60: 1: 0.1)] to obtain ethyl-nor-.
11-oxo-8,9-anhydroerythromycin A
White powder of 6,9-hemiketal (Compound 25) 13
9 mg (yield 65%) was obtained.

[0060]

[Chemical 25]

[0061]

[Example 23] Compound 24 (428 mg) was dissolved in 7 ml of methanol to give diisopropylethylamine (790 m).
g and 4.16 g of isopropyl iodide were added and the temperature was 60 ° C.
Was stirred for 5 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] to give isopropyl-nor-11-oxo-8,9-anhydroerythromycin A6. As a result, 290 mg (yield 64%) of white powder of 9-hemiketal (Compound 26) was obtained.

[0062]

[Chemical formula 26]

[0063]

Example 24 Compound 23 (383 mg) was dissolved in 4 ml of chloroform, and 0.34 ml of propargyl bromide.
Was added and the mixture was stirred at room temperature for 6 hours. The solvent of the reaction solution was distilled off, and then ether was added to precipitate the resulting precipitate. The precipitate was washed with ether and purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (10: 1: 0.1)] to give 11-oxo-.
251 mg (yield 56%) of white powder of 8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide (Compound 27) was obtained.

[0064]

[Chemical 27]

[0065]

Example 25 Compound 4 (300 mg) in methanol 5
Dissolved in ml, diisopropylethylamine 597mg
And 3-chloro-1-butene 456 mg was added to 60
Stir at 40 ° C. for 40 hours. After distilling off the solvent from the reaction solution,
It was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-
Concentrated aqueous ammonia (200: 1: 0.1)] and purified (3-buten-2-yl) -nor-12-O-methyl-
11-oxo-8,9-anhydroerythromycin A
White powder 81 of 6,9-hemiketal (Compound 28)
mg (yield 25%) was obtained.

[0066]

[Chemical 28]

[0067]

Example 26 Compound 4 (300 mg) was dissolved in 5 ml of acetonitrile, and diisopropylethylamine 543 was dissolved.
mg and trifluoromethanesulfonic acid 2-
Add 423 mg of (1,3-difluoropropyl) to give 5
The mixture was stirred at 0 ° C for 30 minutes. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (250: 1: 0.1)] to obtain (1,3-difluoro-2-propyl) -nor-12.
-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 29)
167 mg (yield 50%) of white powder were obtained.

[0068]

[Chemical 29]

[0069]

Example 27 Compound 4 (200 mg) was dissolved in 5 ml of dimethylformamide, and 362 mg of diisopropylethylamine and 1.0 g of 1-bromo-2-fluoroethane.
And 420 mg of sodium iodide were added, and the mixture was stirred at 80 ° C. for 11 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated saline. The ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (250: 1:
0.1)] and purified by 2-fluoroethyl-nor-1
2-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 3
133 mg (yield 63%) of white powder of 0) was obtained.

[0070]

[Chemical 30]

[0071]

Example 28 Compound 4 (250 mg) was added to methanol 4
After dissolving in ml, 0.11 ml of cyclobutanone and 53 mg of sodium cyanoborohydride were added, and the mixture was stirred overnight at room temperature. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] and cyclobutyl-nor-12-O-methyl-11-oxo-8, 192 mg (yield 71%) of white powder of 9-anhydroerythromycin A 6,9-hemiketal (Compound 31) was obtained.

[0072]

[Chemical 31]

[0073]

Example 29 Compound 4 (350 mg) was added to methanol 6
After dissolving in ml, 0.19 ml of cyclopentanone and 74 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give cyclopentyl-nor-12-O-methyl-11-oxo-8, 9
250 mg (65% yield) of white powder of anhydroerythromycin A 6,9-hemiketal (compound 32)
Got

[0074]

[Chemical 32]

[0075]

Example 30 Compound 4 (278 mg) was added to methanol 6
Dissolved in ml, tetrahydrofuran-3-one 144m
g and 59 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature overnight. After distilling off the solvent from the reaction solution,
It was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-
Concentrated aqueous ammonia (150: 1: 0.1)] and purified by 3-tetrahydrofuranyl-nor-12-O-methyl-
11-oxo-8,9-anhydroerythromycin A
White powder 17 of 6,9-hemiketal (Compound 33)
7 mg (yield 58%) was obtained.

[0076]

[Chemical 33]

[0077]

Example 31 Compound 4 (200 mg) was added to methanol 5
dissolved in ml, tetrahydrothiophen-3-one 24
6 mg and 84 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 2 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (230: 1: 0.1)] to give 3-tetrahydrothiophenyl-nor-12-O-.
Methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 34) was obtained as a white powder (146 mg, yield 65%).

[0078]

[Chemical 34]

[0079]

Example 32 Compound 4 (478 mg) was added to methanol 1
Dissolve in 0 ml, 1-benzhydrylazetidine-3-
On 682 mg and sodium cyanoborohydride 1
01 mg was added and the mixture was stirred overnight at room temperature. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-
Methanol-concentrated aqueous ammonia (250: 1: 0.1)]
Purified by (1-benzhydryl-3-azetidinyl) -nor-12-O-methyl-11-oxo-8,9
-Anhydroerythromycin A 6,9-hemiketal (Compound 35) white powder 667 mg (quantitative yield)
Got

[0080]

[Chemical 35]

[0081]

Example 33: Compound 35 (235 mg) was added to acetic acid (6 ml).
Dissolve, add Pearlman's catalyst 50mg, under a hydrogen stream,
Stir overnight at room temperature. After removing the catalyst by filtration, the mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent:
Chloroform-methanol-concentrated aqueous ammonia (10:
1: 0.1)] and purified with 3-azetidinyl-nor-.
12-O-methyl-11-oxo-8,9-anhydroerythromycin A6,9-hemiketal (compound 3
87 mg (yield 41%) of white powder of 6) was obtained.

[0082]

[Chemical 36]

[0083]

Example 34 Compound 4 (250 mg) was added to methanol 5
It was dissolved in ml, 200 mg of 3-oxetanone and 53 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 2.5 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give 3-oxetanyl-nor-12-O-methyl-11-oxo-.
120 mg of a white powder of 8,9-anhydroerythromycin A 6,9-hemiketal (Compound 37) (yield 4
4%).

[0084]

[Chemical 37]

[0085]

Example 35: Compound 4 (205 mg) was dissolved in 5 ml of acetonitrile, and diisopropylethylamine 297 was dissolved.
mg and trifluoromethanesulfonic acid 2,2,2
-Add 650 mg of trifluoroethyl and stir at 50 ° C. overnight. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (200: 1: 0.1)] to prepare 2,2,2-
Trifluoroethyl-nor-12-O-methyl-11-
Oxo-8,9-anhydroerythromycin A 6,
132 mg of white powder of 9-hemiketal (Compound 38)
(Yield 57%) was obtained.

[0086]

[Chemical 38]

[0087]

Example 36 Compound 4 (300 mg) in methanol 7
Dissolved in ml, diisopropylethylamine 543 mg
And 3.09 g of 2-iodobutane were added, and the mixture was stirred at 60 ° C. for 4 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give 2-butyl-nor-12-O-methyl-11-oxo-. 63 mg (yield 20%) of white powder of 8,9-anhydroerythromycin A 6,9-hemiketal (Compound 39) was obtained.

[0088]

[Chemical Formula 39]

[0089]

Example 37 Compound 4 (200 mg) was added to methanol 4
It was dissolved in ml, 0.26 ml of pivalaldehyde and 84 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 40 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (200: 1: 0.1)] to give 2,2-
Dimethylpropyl-nor-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9
128 mg of white powder of hemiketal (compound 40)
(Yield 58%) was obtained.

[0090]

[Chemical 40]

[0091]

Example 38: Compound 4 (250 mg) was dissolved in 6 ml of acetonitrile, and diisopropylethylamine 452 was added.
mg and N- (2-bromoethyl) phthalimide 2.
84 g was added and the mixture was stirred at 50 ° C for one day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-
Methanol-concentrated aqueous ammonia (100: 1: 0.1)]
Purified with 2- (N-phthalimido) ethyl-nor-
12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 4
190 mg (yield 61%) of white powder of 1) was obtained.

Compound 41 (190 mg) was added to methanol 3
Dissolve in ml, 40% methylamine-methanol solution 1
After adding ml, the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (15: 1: 0.1)] to give 2-aminoethyl-nor-12-O-methyl-.
11-oxo-8,9-anhydroerythromycin A
White powder 11 of 6,9-hemiketal (Compound 42)
4 mg (70% yield) was obtained.

[0093]

[Chemical 41]

[0094]

Example 39 Compound 4 (200 mg) was dissolved in 5 ml of acetonitrile, and diisopropylethylamine 362 was added.
mg and α-chloroacetone 777 mg were added, and the mixture was stirred overnight at room temperature. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (60: 1: 0.1)] to give 2-oxopropyl-nor-12-O-methyl-11-oxo. −
196 mg of a white powder of 8,9-anhydroerythromycin A 6,9-hemiketal (Compound 43) (yield 9
1%) was obtained.

[0095]

[Chemical 42]

[0096]

Example 40 A solution of compound 43 (175 mg) in 3 ml of methanol was cooled with ice and sodium borohydride (30 m) was added thereto.
g was added, and the mixture was stirred at room temperature for 7 hours. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (70: 1: 0.1)] to give 2-hydroxypropyl-nor-12-O-methyl-11-oxo. White powder 1 of -8,9-anhydroerythromycin A 6,9-hemiketal (Compound 44)
32 mg (yield 75%) was obtained.

[0097]

[Chemical 43]

[0098]

Example 41 Compound 4 (191 mg) was dissolved in 4 ml of acetonitrile and 4 ml of methanol, 346 mg of diisopropylethylamine and 750 mg of 2-chloroacetamide were added, and the mixture was stirred overnight at 50 ° C. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (60: 1: 0.
1)] and purified by carbamoylmethyl-nor-12-
141 mg (yield 68%) of white powder of O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 45) was obtained.

[0099]

[Chemical 44]

[0100]

Example 42 Compound 4 (605 mg) was dissolved in 6 ml of dimethylformamide, 1.09 g of diisopropylethylamine and 3.48 g of isobutyl bromide were added, and the mixture was stirred at 50 ° C. for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (300: 1: 0)] to give isobutyl-nor-12-O-methyl-11-oxo-.
310 mg of a white powder of 8,9-anhydroerythromycin A 6,9-hemiketal (compound 46) (yield 4
7%).

[0101]

[Chemical formula 45]

[0102]

Example 43: Compound 13 (200 mg) is dissolved in 7 ml of methanol, and α, α'-difluoroacetone 384 is dissolved.
mg and sodium cyanoborohydride (180 mg) were added, and the mixture was stirred at room temperature for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (250: 1: 0.1)] to give (1,3-difluoro-2-propyl) -dinor-.
12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 4
143 mg (yield 64%) of white powder of 7) was obtained.

[0103]

[Chemical formula 46]

[0104]

Example 44 Compound 13 (400 mg) was dissolved in 10 ml of methanol, 492 mg of 3-pentanone and 108 mg of sodium cyanoborohydride were added, and the mixture was stirred overnight at room temperature. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (75: 1: 0.1)] to give 3-pentyl-dinor-12-O-methyl-11-oxo-. 8, 9-
194 mg (yield 44%) of white powder of anhydroerythromycin A 6,9-hemiketal (Compound 48) was obtained.

Compound 48 (194 mg) was dissolved in acetonitrile (6 ml), formaldehyde solution (216 mg), sodium cyanoborohydride (40 mg) and acetic acid (1 drop) were added, and the mixture was stirred at room temperature for 1 hr. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (150: 1: 0.1)] to give 3-pentyl-nor-12-O-methyl-1.
1-oxo-8,9-anhydroerythromycin A
White powder 154 of 6,9-hemiketal (Compound 49)
mg (yield 78%) was obtained.

[0106]

[Chemical 47]

[0107]

Example 45 Compound 13 (500 mg) was dissolved in 5 ml of dimethylformamide, and 461 mg of diisopropylethylamine and 2.4 g of 1,5-dibromopentane.
Was added and the mixture was stirred overnight at 50 ° C. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (300: 1: 0)] and de (dimethylamino) -3'-piperidino-12-O.
184 mg (yield 33%) of white powder of -methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 50) was obtained.

[0108]

[Chemical 48]

[0109]

Example 46 Compound 13 (400 mg) was dissolved in 5 ml of dimethylformamide, and 369 mg of diisopropylethylamine and 1.85 g of 1,4-dibromobutane.
Was added and the mixture was stirred overnight at 50 ° C. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (60: 1: 0.1)] and de (dimethylamino) -3'-pyrrolidino-12-.
124 mg (yield 29%) of white powder of O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 51) was obtained.

[0110]

[Chemical 49]

[0111]

Example 47 Compound 22 (500 mg) was dissolved in 10 ml of methanol, 531 mg of ammonium acetate and 86 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (40: 1: 0.1)] to give 4 ″ -deoxy-4 ″ -amino-12-O-methyl-. 123 mg (yield 25%) of white powder of 11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 52) was obtained.

[0112]

[Chemical 50]

[0113]

Example 48: Compound 22 (200 mg) is dissolved in 10 ml of methanol to give 96 mg of hydroxylamine hydrochloride.
Was added and the mixture was stirred at room temperature for 1 day. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (40: 1: 0.1)] to obtain 4 ″ -deoxy-4 ″ -oximino-12-O-methyl-. 109 mg (yield 53%) of white powder of 11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 53) was obtained.

[0114]

[Chemical 51]

[0115]

Example 49 To a solution of compound 24 (4.90 g) in 1,2-dichloroethane (80 ml) was added dimethylaminopyridine (8.5 g) and benzyloxycarbonyl chloride (8.0 ml) under ice-cooling, and the mixture was stirred as such for 1 hour. It was stirred at room temperature for a further 19 hours. Water was added to the reaction solution, which was extracted with dichloromethane and washed with saturated saline. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue is purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (70: 1: 0)] to give N-demethyl-2 '.
1.38 g of white powder of -O, 4 "-O, 3'-N-tris (benzyloxycarbonyl) -11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 54) (yield 18%).

A solution of compound 54 (600 mg) in 10 ml of dimethylformamide was added to sodium hydride (3) under ice cooling.
3 mg was added. After stirring for 15 minutes, ethyl iodide 0.0
85 ml was added and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0)].
Purified by N-demethyl-2'-O, 4 "-O, 3 '
-N-tris (benzyloxycarbonyl) -12-O
-Ethyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 55) was obtained as a white powder 305 mg (yield 53%).

Compound 55 (300 mg) in ethanol 8
50 ml of 10% palladium carbon was added to the ml solution,
The mixture was stirred overnight at room temperature under a hydrogen stream. After that, 228 mg of formaldehyde solution was added, and the mixture was further stirred under a hydrogen stream for 6 hours. The reaction solution was filtered and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (4
0: 1: 0.1)] and 12-O-ethyl-1.
1-oxo-8,9-anhydroerythromycin A
White powder 146 of 6,9-hemiketal (Compound 56)
mg (yield 74%) was obtained.

[0118]

[Chemical 52]

[0119]

Example 50 To a solution of compound 54 (219 mg) in 3 ml of dimethylformamide was added sodium hydride 1 under ice-cooling.
2 mg was added. After stirring for 15 minutes, 0.047 ml of benzyl bromide was added and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The ethyl acetate solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 2)] and N-demethyl-2′-O, 4 ″ -O, 3′-N-tris ( Benzyloxycarbonyl) -12-O-benzyl-11-
Oxo-8,9-anhydroerythromycin A 6,
179 mg of white powder of 9-hemiketal (Compound 57)
(Yield 75%) was obtained.

Compound 57 (175 mg) in ethanol 4
27 mg of 10% palladium carbon was added to the ml solution,
The mixture was stirred overnight at room temperature under a hydrogen stream. After that, add 71 mg of formaldehyde solution, and further under a hydrogen stream for 8
Stir for hours. The reaction solution was filtered and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent:
Chloroform-methanol-concentrated aqueous ammonia (70:
1: 0.1)] and 12-O-benzyl-11
-Oxo-8,9-anhydroerythromycin A
White powder 121 of 6,9-hemiketal (Compound 58)
mg (quantitative yield) was obtained.

[0121]

[Chemical 53]

[0122]

Example 51 A solution of compound 54 (264 mg) in 3 ml of dimethylformamide was added to sodium hydride 1 under ice cooling.
9 mg was added. After stirring for 15 minutes, 0.070 ml of n-propyl iodide was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The ethyl acetate solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-n-hexane (1: 2)] and N-demethyl-2′-O, 4 ″ -O, 3′-N-tris ( Benzyloxycarbonyl) -12-O-propyl-11-
Oxo-8,9-anhydroerythromycin A 6,
133 mg of white powder of 9-hemiketal (Compound 59)
(Yield 48%) was obtained.

Ethanol 4 of compound 59 (133 mg)
20 mg of 10% palladium carbon was added to the ml solution,
The mixture was stirred overnight at room temperature under a hydrogen stream. After that, add 96 mg of formaldehyde solution, and under a hydrogen stream, add 5 more
Stir for hours. The reaction solution was filtered and the solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent:
Chloroform-methanol-concentrated aqueous ammonia (70:
1: 0.1)] and 12-O-propyl-11.
-Oxo-8,9-anhydroerythromycin A
White powder of 6,9-hemiketal (Compound 60) 80 m
g (yield 91%) was obtained.

[0124]

[Chemical 54]

[0125]

Example 52 To a solution of the compound 6 (10.5 g) in 70 ml of dichloromethane, 4.5 ml of pyridine and 2.6 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol (250: 1)] to give isopropyl-nor-2'-O-acetyl-12-O-methyl-11-oxo-8,9. -Anhydroerythromycin A 6,9-
8.5 g (yield 76%) of white powder of hemiketal (compound 61) was obtained.

[0126]

Example 53 To a solution of compound 61 (8.5 g) in 70 ml of dichloromethane was added 5.20 g of dimethylaminopyridine.
And 1,1'-thiocarbonyldiimidazole 6.33 g
Was added and the mixture was stirred at room temperature for 3 days. After adding 3 ml of concentrated aqueous ammonia to the reaction solution and stirring for 15 minutes, dichloromethane was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue is subjected to silica gel chromatography [developing solvent:
Chloroform-methanol (400: 1)] and isopropyl-nor-2'-O-acetyl-4 "-O.
-Thiocarbonylimidazolyl-12-O-methyl-1
1-oxo-8,9-anhydroerythromycin A
White powder of 6,9-hemiketal (Compound 62) 7.5
0 g (77% yield) was obtained.

A solution of compound 62 (350 mg), triphenyltin hydride (243 mg) and α, α'-azobis (isobutyronitrile) 13 mg in toluene (7 ml) was added to 2 parts.
Heated to reflux for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: ethyl acetate-hexane (1: 2)] to give isopropyl-nor-2′-O-acetyl-4 ″ -deoxy-1.
2-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (compound 6
156 mg (yield 52%) of white powder of 3) was obtained.

Compound 63 (153 mg) was added to methanol 3
ml and dichloromethane 0.5 ml were added and dissolved, saturated aqueous sodium hydrogen carbonate solution 0.3 ml was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] to give isopropyl-nor-4 ″ -deoxy-12-O-methyl-11. 129 mg (yield 89%) of white powder of -oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 64) was obtained.

[0129]

[Chemical 55]

[0130]

Example 54 A solution of compound 64 (3.60 g) and 2.0 g of sodium acetate in 70 ml of 80% methanol / water was heated to 55 ° C., and 1.85 g of iodine was added under stirring. Stir for 1 hour at this temperature, during which time the solution is pH
In order to keep it at 8 to 9, an appropriate amount of 1N sodium hydroxide aqueous solution was added. The reaction solution was poured into 50 ml of water containing 3 ml of concentrated aqueous ammonia, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (15: 1: 0.
1)] and white powder of de (N-methyl) -4 ″ -deoxy-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 65). 712 mg (21% yield) was obtained.

Ethanol 1 of Compound 65 (430 mg)
Formaldehyde solution (528 mg), acetic acid (0.070 ml) and 10% palladium carbon (90 mg) were added to the 0 ml solution, and the mixture was stirred at room temperature under a hydrogen stream for 1 day. The reaction solution was filtered, the solvent was distilled off, saturated aqueous sodium hydrogencarbonate was added to the resulting residue, and the mixture was extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] to give 4 ″ -deoxy-12-O-methyl-11-oxo-8. As a result, 327 mg (yield 74%) of white powder of 9,9-anhydroerythromycin A 6,9-hemiketal (Compound 66) was obtained.

[0132]

[Chemical 56]

[0133]

Example 55 Compound 65 (278 mg) was dissolved in 5 ml of methanol to prepare diisopropylethylamine 0.56.
ml and ethyl iodide 0.19 ml were added, and the mixture was stirred at room temperature for 5 days. After distilling off the solvent, the reaction solution was diluted with chloroform and washed with water and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (100: 1: 0.1)] and ethyl-nor-4 ″ -deoxy-12-O-methyl-11. Thus, 149 mg (yield 51%) of white powder of -oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 67) was obtained.

[0134]

[Chemical 57]

[0135]

Example 56 Compound 65 (591 mg) was dissolved in 10 ml of methanol, and diisopropylethylamine 1.0 was added.
Add 9 g and 6.23 g of 2-iodobutane to give 50
The mixture was stirred at 0 ° C for 4 days. The reaction solution was diluted with chloroform after removing the solvent, and washed with water and saturated saline.
This chloroform solution is dried over anhydrous sodium sulfate,
The solvent was distilled off. The obtained residue is subjected to silica gel chromatography [developing solvent: chloroform-methanol (40
0: 1)] to give 2-butyl-nor-4 ″ -deoxy-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiketal (Compound 68) white. 261 mg of powder (40% of yield) were obtained.

[0136]

[Chemical 58]

[0137]

Example 57: Compound 6 (187 mg) and fumaric acid 2
8.5 mg was dissolved in 0.3 ml of methanol while hot, 1.0 ml of isopropyl alcohol was added, and the mixture was allowed to stand at room temperature to precipitate crystals. The precipitated crystals were collected by filtration, and colorless rod crystals of isopropyl-nor-12-O-methyl-11 were obtained.
-Oxo-8,9-anhydroerythromycin A
6,9-hemiketal fumarate monohydrate (compound 6
9) Obtained 139 mg. m. p. 135-137 ° C., elemental analysis C ₄₂ H ₇₃ NO ₁₅ Theoretical value (%): C60.6
3, H8.84, N1.68 Found (%): C60.
67, H8.78, N1.71

[Chemical 59]

[0138]

Example 58: Compound 6 (100 mg) and succinic acid 1
5.6 mg was dissolved in 0.3 ml of methanol while hot, 1.0 ml of isopropyl alcohol was added, and the mixture was allowed to stand at room temperature to precipitate crystals. The precipitated crystals were collected by filtration, and colorless rod crystals of isopropyl-nor-12-O-methyl-11 were obtained.
-Oxo-8,9-anhydroerythromycin A
6,9-hemiketal succinate (Compound 70) 26m
g was obtained. m. p. 115-121 ° C

[Chemical 60] Compounds 2 to 70 obtained in Examples 1 to 58 (however,
Compounds 24, 41, 48, 54, 55, 57, 59, 6
Various physical property values (except 1-63 and 65) are summarized in Table 1 and Table 2.

[0139]

[Table 1]

[Table 2]

[0140]

Test Example 1 The motilin receptor binding test was carried out by the following method [V. Bormans et al., Regul, Pe
ptides, 15, 143 (1986)]. The duodenum was extracted from the slaughtered rabbit, and the mucous membrane was peeled from the muscularis layer, and then HO in 50 mM Tris solution (pH 7.4).
A protein solution was obtained by carrying out a mogenizing process. ¹²⁵ I Label Motilin (purchased from Otsuka Assay Laboratories) 25 pM and 2 protein solutions
After incubating at 5 ° C for 120 minutes, the radioactivity in the protein was measured with a γ counter, and the radioactivity when nothing was added and the radioactivity when a large excess of motilin (1 × 10 ^-7 M) was added. The difference in activity was defined as specific binding. Analyte potency is the concentration of drug that reduces specific binding to 50% IC ₅₀ (M)
Expressed as The drug was dissolved in DMSO solution and added to the protein solution (final DMSO concentration was 1%). Further, in the experiment for examining the resistance to acid, the drug was dissolved in a hydrochloric acid solution (pH 2.5), allowed to stand at room temperature for 120 minutes, and then added to the protein solution for use in the experiment.

As a result, IC ₅₀ (M) in DMSO solution
Is EM-523 2.6 × 10 ^−9, whereas compound 6 is 4.
It was 1 × 10 ⁻⁹ , and the activities of these two samples were equivalent (Table 3). In a hydrochloric acid solution, the IC ₅₀ (M) of EM-523 is 2.
It was 6 × 10 ⁻⁷ , which was 100 times lower than that of the DMSO solution, but the IC ₅₀ (M) of Compound 6 was 9.1 × 10 7.
^-9 , which was almost the same as the DMSO solution (Table 3). From this, it was proved that Compound 6 was less likely to be decomposed by an acid than EM-523.

[0142]

[Table 3]

[0143]

[Test Example 2] The digestive tract contraction movement was measured by the following method [Tomo Itoh, Journal of Japan Smooth Muscle Society, 13, 33 (197).
6)]. A beagle dog having a body weight of about 10 kg was previously subjected to laparotomy under general anesthesia, and a force transducer was chronically sewn on the serosa surface of the antrum of the stomach, duodenum and jejunum in a direction in which contraction of each cricoid muscle could be measured. A medical silicone tube was placed in the stomach to directly administer the drug into the stomach. The force transducer leads and silicone tubing were withdrawn from the back and secured to the skin. After surgery the dogs were housed in individual experimental cages and fed once daily.

The principle of the force transducer is
When the digestive tract of the sewn part contracts and bending strain is applied to the transducer, a waveform proportional to the force is recorded with a pen and recorded on the oscillograph.The conductor from the force transducer is oscillographed. The contraction waveform can be immediately recorded by connecting to. The contractile movement of the digestive tract is roughly classified into the postprandial period and the fasting period based on the contraction pattern.

The experiment was started 2 weeks after the operation, and was performed in the fasting period, and in the resting period in which there were no gastric contractions in the stomach. That is, about 1 via a silicone tube placed in the stomach
The sample was injected directly into the stomach over 0 seconds. The drug was dissolved in ethanol in advance and diluted with physiological saline to make the total amount 3 ml.

In order to quantitatively express the gastrointestinal contraction motility promoting effect, the area between the baseline and the contraction waveform when the motion in the stomach is at rest is referred to as Motor Index (MI), which is used as an index of gastric motility [Inatomi Et al., J. Phar
macol. Exp. Ther. , 251, 707 (1
989)]. MI transmits the signal from the force transducer sewn on the stomach to a computer (PC-980).
1, NEC) and calculated. The gastric momentum of fasting-propagated contractions that naturally occurs in the fasting period is MI = 100 to 200 when expressed by MI calculated by this method. So M
The dose of the drug required to express I = 150 was set to MI _{150 and used} as an index of the gastrointestinal motility promoting effect of the drug.

By intragastric administration, EM-523
And compound 6 each show a gastrointestinal motility promoting action,
Each MI ₁₅₀ had 14.6 μg / kg and 3.
It was 8 μg / kg. Compound 6 showed a gastrointestinal motility promoting action about 4 times stronger in intragastric administration than EM-523.

[0148]

INDUSTRIAL APPLICABILITY The erythromycin derivative of the present invention having a gastrointestinal motility promoting activity is characterized in that it is remarkably less decomposed by an acid than conventionally known erythromycin derivatives. Therefore, the erythromycin derivative of the present invention, even when used by oral administration, unlike the known erythromycin derivative, is not significantly decomposed by gastric acid, and thus exhibits a strong action for promoting gastrointestinal motility.

Claims (1)

[Claims] 1. A general formula: Wherein R ₁ represents a hydrogen atom or an acyl group, R ₂ and R ₃ are the same or different and represent a hydrogen atom, a hydroxyl group, an acyloxy group, an amino group or together = O, = NOR ₁₀
Indicates. Here, R ₁₀ represents a hydrogen atom or a lower alkyl group. R ₄ is a hydrogen atom or a lower alkyl group, Y is -NR ₅ R ₆ or ^{_{-N + R 7 R 8 R 9}} X - indicating each. Here, R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each may have a hydrogen atom or a substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group or A heterocyclic group having a 3- to 7-membered ring containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom, and X represents an anion. Also, R ₅ and R
₆ , R ₇ and R ₈ may together form an azacycloalkyl group with the adjacent nitrogen atom. ]
Or a salt thereof.